1. Field of the Invention
The present invention relates generally to the field of drug delivery systems. In particular, the present invention relates to osmotic pump systems, devices, kits and associated methods for shortening the time interval between implantation of the osmotic pump system and delivery of a pharmaceutical agent to the patient.
2. Description of the Related Art
Since the beginning of modern medicine, drugs have been administered orally. Patients have taken pills as recommended by their physician. The pills must pass through the digestive system and then the liver before they reach their intended delivery site (e.g., the vascular system). The actions of the digestive tract and the liver often reduce the efficacy of medication; furthermore, medications delivered systemically sometimes cause undesirable side effects. Over the course of the past few decades, drug delivery technology and administration has evolved from oral delivery to site-specific delivery. In addition to the oral route of administration, drugs are also routinely administered via the vascular system (intravenous or IV). Intravenous drug delivery has the advantage of bypassing the acidic and enzymatic action of the digestive system. Unfortunately, IV administration requires the use of a percutaneous catheter or needle to deliver the drug to the vein. The percutaneous site requires extra cleanliness and maintenance to minimize the risk of infection. Infection is such a significant risk that IV administration is often limited to a number of weeks, at most. In addition, the patient must wear an external pump connected to the percutaneous catheter.
The next step in the evolution of drug delivery was the implanted pump. The implanted pump is a device that is completely implanted under the skin of a patient, thereby negating the need for a percutaneous catheter. These implanted pumps provide the patient with a drug at a constant or a programmed delivery rate. Constant rate or programmable rate pumps are based on either phase-change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-rate pump is well suited for long-term implanted drug delivery. If changes to the infusion rate are expected, a programmable pump may be used in place of the constant rate pump. Fully implanted constant rate and programmable rate infusion pumps have been sold in the United States for human use since the late 1970s and early 1980s, respectively. Two problems associated with such 1970s and 1980s vintage constant rate and programmable rate infusion pumps relate to their size and their cost. Current implantable constant rate and programmable pumps are about the size and shape of hockey pucks, and they typically are sold to the hospital for $5,000-$9,000. The current implantable pumps must be implanted in the Operating Room under general anesthesia, which further increases costs, as well as the risk, and discomfort to the patient. The size and cost of such pumps has proven to be a substantial barrier to their use, and they are rarely used to deliver medication. An added drawback of phase-change and peristaltic pumps is that they must be refilled with drug every 3-8 weeks. Refills constitute an added burden to the caregiver, and add further costs to an already overburdened healthcare system. The burden associated with such refills, therefore, further limits the use of phase-change and peristaltic pumps.
In the 1970s, a new approach toward implanted pump design was commercialized for animal use only. The driving force of the pumps based upon this new approach utilized the principle of osmosis. Osmotic pumps may be much smaller than other constant rate or programmable pumps, because their infusion rate can be very low. A recent example of such a pump is described listed in U.S. Pat. No. 5,728,396. This patent discloses an implantable osmotic pump that achieves a sustained delivery of leuprolide. The pump includes an impermeable reservoir that.is divided into a water-swellable agent chamber and a drug chamber. Fluid from the body is imbibed through a semi permeable plug into the water-swellable agent chamber and the drug is released through a diffusion outlet at a substantially constant rate.
Once implanted, however, conventional osmotic pump systems do not begin infusing drug into the patient immediately. Indeed, the semi permeable plug, initially dry before implantation, must first become thoroughly hydrated with the patient""s bodily fluids after implantation before the pump will deliver the drug at the intended and designed infusion rate. This time interval between implantation and full hydration of the semi permeable plug is non-trivial, and is usually on the order of several hours to 2-4 days. In the case wherein the pump contains pain medication, this means that the patient must endure a long delay before the pump begins to work as designed (i.e., at its steady state infusion rate) and.provides the expected relief. Often, therefore, the surgeon must provide the patient with additional medication to bridge the gap between implantation of the osmotic pump system and full operation thereof. Patients, therefore, would be well served with osmotic pump delivery systems that would begin infusing drug at the intended rate immediately or soon after implantation.
Further adding to this delay is the catheter attached to the osmotic pump. The catheter is designed to carry the drug from the osmotic pump to the intended delivery site within the patient, whether a subcutaneous, epidural, subdural, subarachnoid, intravenous or intraventricular location, for example. The infusion lumen of the catheter defines an internal volume called the dead volume of the catheter. Upon first implantation of a osmotic pump system, the drug pushed out of the pump""s drug compartment must flow the entire length of the catheter before reaching the intended delivery site. The time required for the drug to do so further adds to the already long hydration delay and further delays any benefit to be derived from using an implantable pump system. Patients would also be well served, therefore, with methods, devices and systems to shorten or eliminate the delay in delivery of the drug attributable to the dead volume of the catheter.
A conventional osmotic pump system, however, does start to infuse some amount of drug as the semi permeable plug hydrates. However, the amount of drug that is infused as the plug hydrates is often unknown and unpredictable. Indeed, the rate at which the plug hydrates may vary upon many factors, such as the composition and thickness of the semi permeable plug, as well as the hydration levels of the implantation site of the system within the patient. Therefore, it becomes difficult for the surgeon to estimate the effective drug delivery rate in the first few hours and days after implantation. This may render the surgeon overly conservative or unduly aggressive when administering pain medication to bridge the aforementioned gap between initial implantation and full hydration of the semi permeable plug. Indeed, the surgeon may administer less (or more) drug than the therapeutically optimal amount. This is because the surgeon has no way of reliably estimating the current amount of drug being infused into the patient soon after implantation of the osmotic device, as the semi permeable plug thereof typically does not hydrate at a constant or predictable rate in all situations.
There is believed to have been a long felt need for osmotic pump systems, devices and associated methods in which the initial delivery rate of pharmaceutical agent is predictable, and occurs at substantially the designed steady state infusion rate.
It is an object of the present invention, therefore, to provide osmotic pump delivery systems that begin infusing a pharmaceutical agent at the intended rate immediately or soon after implantation. It is a further object of the present invention to provide methods, devices and systems to shorten or eliminate the delay in delivery of the drug caused by the dead volume of the catheter. It is a still further object of the present invention to provide osmotic pump systems, devices and associated methods in which the initial delivery rate of pharmaceutical agent is predictable, and occurs at substantially the intended steady state rate.
In accordance with the above-described objects and those that will be mentioned and will become apparent below, a kit, according to an embodiment of the present invention, comprises a liquid tight container enclosing an implantable osmotic pump, the pump including a semipermeable membrane; a salt tablet, and a saturated saline solution, the saline solution being in fluid contact at least with the salt tablet and the semipermeable membrane.
According to further embodiments, a catheter may be attached to the osmotic pump. The catheter may include a distal valve mechanism adapted to prevent fluid back flow into the catheter. The saturated saline solution may be in fluid contact with the osmotic pump and the tablet. The container may be or may include a flexible fluid-tight bag made of or including, for example, polyethylene, PET, PETG and/or a gas permeable barrier film. The osmotic pump may be preloaded with a pharmaceutical agent. For example, the osmotic pump may be preloaded with one or more pharmaceutical agents for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy and/or other pharmaceutical therapies. In the case of pain therapy, the pharmaceutical agent pre-loaded into the pump system may include one or more of the drugs fentanyl, sufentanil and clonidine, and mixtures thereof. The catheter may include a flushing valve near a proximal end thereof. The catheter may be formed of an elastomeric, polymeric or composite materials such as silicone or polyurethane and the flushing valve may is include or be formed as a longitudinal slit in the catheter. The kit may further include an ampoule containing a pharmaceutical agent therein, and a syringe fitted with an extension tube, a distal end of which is dimensioned to fit within the proximal flushing valve of the catheter.
The present invention may also be seen as a method of packaging an implantable osmotic pump system, the system including an implantable osmotic pump including a semipermeable membrane at one end and a catheter fitted to another end thereof, comprising the steps of disposing the osmotic pump in a liquid tight container; disposing a salt tablet within the container; at least partially filling the container with a saline solution such that the solution is in fluid contact at least with the semipermeable membrane and the salt tablet, and sealing the container. A step of sterilizing the sealed container may also be carried out. The disposing, filling and sealing steps may also be carried out aseptically.
Alternatively, the present invention may be viewed as a method of shortening a time from implantation of an osmotic pump system to delivery of a first pharmaceutical agent to a patient, the osmotic pump system including a semipermeable membrane at one end and a catheter including an infusion lumen at another end thereof, the method comprising the steps of pre-hydrating the semipermeable membrane prior to implantation of the pump system into the patient; flushing a dead volume of the infusion lumen with a second pharmaceutical agent, and implanting the osmotic pump system.
According to further embodiments, the pre-hydrating step may include the step of packaging the osmotic pump system in a liquid tight container including a saline solution. The packaging step may include a step of placing a salt tablet in the saline solution to maintain the solution in a saturated state. Alternatively, the osmotic pump system may include an impermeable membrane covering the semipermeable membrane and defining an interstitial hydration compartment therewith, the hydration compartment containing a saturated saline solution therein and the method may further comprise the step of breaching the impermeable membrane prior to the implanting step. The catheter may include a proximal flushing valve, and the flushing step may include the step of injecting the pharmaceutical agent into the infusion lumen through the proximal flushing valve. The injecting step may include the steps of drawing a sufficient amount of the pharmaceutical agent to fill the dead volume of the infusion lumen into a syringe fitted with an extension tube, disposing a free end of the extension tube into the proximal flushing valve, depressing a plunger of the syringe and removing the extension tube from the proximal flushing valve.
The present invention is also an implantable osmotic pump system, comprising a pump housing having a proximal and a distal end, the pump housing including a pharmaceutical agent compartment and an osmotic agent compartment separated by a movable piston; a semipermeable membrane fitted to the proximal end; an impermeable membrane disposed over and away from the semipermeable membrane to define a fluid tight hydration compartment therewith and a saturated saline solution within the hydration compartment.
According to further embodiments, a salt tablet may be disposed in the hydration compartment. The impermeable barrier may include titanium, stainless steel, platinum, platinum-iridium, PET and/or PETG, for example. The impermeable membrane may be configured to be breached with a lancet prior to implantation of the osmotic pump system in a patient. The pharmaceutical agent compartment may be preloaded with a pharmaceutical agent. For example, the pharmaceutical agent may include one or more of the following drugs: fentanyl, sufentanil and clonidine. The osmotic pump system may be preloaded with one or more pharmaceutical agents for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy and/or other pharmaceutical therapies. A catheter may be attached to the distal end of the pump housing, the attached catheter being in fluid communication with the pharmaceutical agent compartment. The catheter may include an infusion lumen and an elastomeric proximal flushing valve. The catheter may include a distal valve mechanism adapted to prevent fluid back flow into the catheter.
The present invention is also a kit comprising an implantable osmotic pump system, comprising a pump housing having a proximal and a distal end, the pump housing including a pharmaceutical agent compartment and an osmotic agent compartment separated by a movable piston; a semipermeable membrane fitted to the proximal end; an impermeable membrane disposed over and away from the semipermeable membrane to define a fluid tight hydration compartment therewith and a saturated saline solution within the hydration compartment, and a lancet adapted to breach the impermeable barrier.
A salt tablet may be disposed in the hydration compartment. The impermeable barrier may include titanium and/or stainless steel, platinum, platinum-iridium, PET and/or PETG, for example. The impermeable membrane may be configured to be breached with a lancet prior to implantation of the osmotic pump system in a patient. The pharmaceutical agent compartment may be preloaded with a pharmaceutical agent. The pharmaceutical agent may include fentanyl, sufentanil and/or clonidine. The osmotic pump system may be preloaded with one or more pharmaceutical agents for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy and/or other pharmaceutical therapies. A catheter may be attached to the distal end of the pump housing and in fluid communication with the pharmaceutical agent compartment. The catheter may include an infusion lumen and an elastomeric proximal flushing valve. The catheter may include a distal valve mechanism adapted to prevent fluid back flow into the catheter. A syringe adapted to inject pharmaceutical agent into the infusion lumen through the proximal valve may also be included in the kit. The syringe may include an extension tube fitted thereto, the free end thereof being adapted to fit into the proximal flushing valve. An ampoule may be included in the kit, the ampoule containing a sufficient volume of pharmaceutical agent to flush the infusion lumen prior to implantation of the osmotic pump system.
The present invention may also be viewed as a method of shortening a time interval between implantation of a pump system and first delivery of a pharmaceutical agent to the patient, the pump system including a pump housing having a proximal end and a distal end, the distal end having a catheter attached thereto, the catheter including an infusion lumen defining a dead volume, the method comprising the steps of at least partially filling the dead volume of the infusion lumen with the pharmaceutical agent prior to implantation of the pump system into the patient, and implanting the pump system into the patient.
The pump system may be an osmotic pump system including a semi permeable membrane fitted to the proximal end of the pump housing and wherein the method further comprises the step of pre-hydrating the semi permeable membrane prior to the implanting step. The pre-hydrating step may pre-hydrate the semi permeable membrane with a saturated saline solution.
According to a still further embodiment of the present invention, a method of shortening a time from implantation of a pump system to first delivery of a first pharmaceutical agent to a patient, the pump system including a pump housing containing a first pharmaceutical agent and a catheter including an infusion lumen, comprises the steps of flushing a dead volume of the infusion lumen with a second pharmaceutical agent, and implanting the pump system.
The first and second pharmaceutical agents may be the same or different pharmaceutical agents. The catheter may include a proximal flushing valve, and the flushing step may include the step of injecting the second pharmaceutical agent into the infusion lumen through the proximal flushing valve. The injecting step may include the steps of drawing a sufficient amount of the second pharmaceutical agent to fill the dead volume of the infusion lumen into a syringe fitted with an extension tube, disposing a free end of the extension tube into the proximal flushing valve, depressing a plunger of the syringe and removing the extension tube from the proximal flushing valve.